Integrated metagenomic and metabolomic analysis reveals distinct gut-microbiome-derived phenotypes in early-onset colorectal cancer

Objective The incidence of early-onset colorectal cancer (EO-CRC) is steadily increasing. Here, we aimed to characterise the interactions between gut microbiome, metabolites and microbial enzymes in EO-CRC patients and evaluate their potential as non-invasive biomarkers for EO-CRC. Design We performed metagenomic and metabolomic analyses, identified multiomics markers and constructed CRC classifiers for the discovery cohort with 130 late-onset CRC (LO-CRC), 114 EO-CRC subjects and age-matched healthy controls (97 LO-Control and 100 EO-Control). An independent cohort of 38 LO-CRC, 24 EO-CRC, 22 LO-Controls and 24 EO-Controls was analysed to validate the results. Results Compared with controls, reduced alpha-diversity was apparent in both, LO-CRC and EO-CRC subjects. Although common variations existed, integrative analyses identified distinct microbiome–metabolome associations in LO-CRC and EO-CRC. Fusobacterium nucleatum enrichment and short-chain fatty acid depletion, including reduced microbial GABA biosynthesis and a shift in acetate/acetaldehyde metabolism towards acetyl-CoA production characterises LO-CRC. In comparison, multiomics signatures of EO-CRC tended to be associated with enriched Flavonifractor plauti and increased tryptophan, bile acid and choline metabolism. Notably, elevated red meat intake-related species, choline metabolites and KEGG orthology (KO) pldB and cbh gene axis may be potential tumour stimulators in EO-CRC. The predictive model based on metagenomic, metabolomic and KO gene markers achieved a powerful classification performance for distinguishing EO-CRC from controls. Conclusion Our large-sample multiomics data suggest that altered microbiome–metabolome interplay helps explain the pathogenesis of EO-CRC and LO-CRC. The potential of microbiome-derived biomarkers as promising non-invasive tools could be used for the accurate detection and distinction of individuals with EO-CRC.

[1]  Peng Zhang,et al.  Cancer-derived exosomal HSPC111 promotes colorectal cancer liver metastasis by reprogramming lipid metabolism in cancer-associated fibroblasts , 2022 .

[2]  Bangmao Wang,et al.  Microbial metabolite deoxycholic acid promotes vasculogenic mimicry formation in intestinal carcinogenesis , 2021, Cancer science.

[3]  Xinxiang Li,et al.  Dysbiosis of human gut microbiome in young-onset colorectal cancer , 2021, Nature Communications.

[4]  L. F. Barbisan,et al.  Synbiotic supplementation attenuates the promoting effect of indole-3-carbinol on colon tumorigenesis. , 2021, Beneficial microbes.

[5]  Wei Yan,et al.  Fusobacterium nucleatum Acts as a Pro-carcinogenic Bacterium in Colorectal Cancer: From Association to Causality , 2021, Frontiers in Cell and Developmental Biology.

[6]  Jie Hong,et al.  Enterotoxigenic Bacteroides fragilis promotes intestinal inflammation and malignancy by inhibiting exosomes-packaged miR-149-3p. , 2021, Gastroenterology.

[7]  Sean M. Kearney,et al.  Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians , 2021, Nature.

[8]  R. Hu,et al.  Overproduction of Gastrointestinal 5-HT Promotes Colitis-Associated Colorectal Cancer Progression via Enhancing NLRP3 Inflammasome Activation , 2021, Cancer Immunology Research.

[9]  M. Kalady,et al.  Fusobacterium Nucleatum Promotes the Development of Colorectal Cancer by Activating a Cytochrome P450/Epoxyoctadecenoic Acid Axis via TLR4/Keap1/NRF2 Signaling , 2021, Cancer Research.

[10]  G. Zeng,et al.  Porphyromonas gingivalis Promotes Colorectal Carcinoma by Activating the Hematopoietic NLRP3 Inflammasome , 2021, Cancer Research.

[11]  Shiyi Tian,et al.  Xylitol enhances synthesis of propionate in the colon via cross-feeding of gut microbiota , 2021, Microbiome.

[12]  Dandan Wu,et al.  Mitophagy protein PINK1 suppresses colon tumor growth by metabolic reprogramming via p53 activation and reducing acetyl-CoA production , 2021, Cell Death & Differentiation.

[13]  Z. Gong,et al.  Perfluorooctane Sulfonate Promotes Doxycycline-induced Liver Tumor Progression in Male Krasv12 Transgenic Zebrafish. , 2021, Environmental research.

[14]  M. Schulze,et al.  Association of Pre-diagnostic Antibody Responses to Escherichia coli and Bacteroides fragilis Toxin Proteins with Colorectal Cancer in a European Cohort , 2021, Gut microbes.

[15]  C. Trautwein,et al.  The gut bacterium Extibacter muris produces secondary bile acids and influences liver physiology in gnotobiotic mice , 2020, Gut microbes.

[16]  P. Moayyedi,et al.  Novel fecal biomarkers that precede clinical diagnosis of ulcerative colitis. , 2020, Gastroenterology.

[17]  S. Ogino,et al.  Rising incidence of early-onset colorectal cancer — a call to action , 2020, Nature Reviews Clinical Oncology.

[18]  U. Ellis,et al.  Risk Factors Associated With Young-Onset Colorectal Adenomas and Cancer: A Systematic Review and Meta-Analysis of Observational Research , 2020, Cancer control : journal of the Moffitt Cancer Center.

[19]  A. Sgoifo,et al.  Bifidobacterium adolescentis as a key member of the human gut microbiota in the production of GABA , 2020, Scientific Reports.

[20]  M. Surette,et al.  The Gut Microbiota and Unhealthy Aging: Disentangling Cause from Consequence. , 2020, Cell host & microbe.

[21]  Xuewei Zhu,et al.  A human-origin probiotic cocktail ameliorates aging-related leaky gut and inflammation via modulating microbiota-taurine-tight junction axis. , 2020, JCI insight.

[22]  A. Jemal,et al.  Colorectal cancer statistics, 2020 , 2020, CA: a cancer journal for clinicians.

[23]  P. Dorrestein,et al.  Dietary prebiotics alter novel microbial dependent fecal metabolites that improve sleep , 2020, Scientific Reports.

[24]  Takashi Sato,et al.  Oral Administration of Flavonifractor plautii Strongly Suppresses Th2 Immune Responses in Mice , 2020, Frontiers in Immunology.

[25]  Kwok-Kin Wong,et al.  Activation of Oxidative Stress Response in Cancer Generates a Druggable Dependency on Exogenous Non-essential Amino Acids. , 2019, Cell metabolism.

[26]  Vineet K. Sharma,et al.  Association of Flavonifractor plautii, a Flavonoid-Degrading Bacterium, with the Gut Microbiome of Colorectal Cancer Patients in India , 2019, mSystems.

[27]  Gang Wang,et al.  Role of SCFAs in gut microbiome and glycolysis for colorectal cancer therapy , 2019, Journal of cellular physiology.

[28]  Jun Yu,et al.  Gut microbiota in colorectal cancer: mechanisms of action and clinical applications , 2019, Nature Reviews Gastroenterology & Hepatology.

[29]  E. Rimm,et al.  Role of Dietary Flavonoid Compounds in Driving Patterns of Microbial Community Assembly , 2019, mBio.

[30]  D. Grundy,et al.  Deoxycholic acid activates colonic afferent nerves via 5-HT3 receptor dependent and independent mechanisms. , 2019, American journal of physiology. Gastrointestinal and liver physiology.

[31]  I. Selvi,et al.  The importance of plasma arginine level and its downstream metabolites in diagnosing prostate cancer , 2019, International Urology and Nephrology.

[32]  U. Ladabaum,et al.  Cost-Effectiveness and National Effects of Initiating Colorectal Cancer Screening for Average-Risk Persons at Age 45 Years Instead of 50 Years. , 2019, Gastroenterology.

[33]  Tomoyoshi Soga,et al.  Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer , 2019, Nature Medicine.

[34]  A. Jemal,et al.  Emerging cancer trends among young adults in the USA: analysis of a population-based cancer registry. , 2019, The Lancet. Public health.

[35]  Dongmei Ai,et al.  Using Decision Tree Aggregation with Random Forest Model to Identify Gut Microbes Associated with Colorectal Cancer , 2019, Genes.

[36]  Karsten Zengler,et al.  GABA Modulating Bacteria of the Human Gut Microbiota , 2018, Nature Microbiology.

[37]  Xin-hua Liang,et al.  Porphyromonas gingivalis Promotes 4-Nitroquinoline-1-Oxide-Induced Oral Carcinogenesis With an Alteration of Fatty Acid Metabolism , 2018, Front. Microbiol..

[38]  Lanjuan Li,et al.  Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma , 2018, Gut.

[39]  C. Franceschi,et al.  Inflammaging: a new immune–metabolic viewpoint for age-related diseases , 2018, Nature Reviews Endocrinology.

[40]  C. Flowers,et al.  Colorectal cancer screening for average‐risk adults: 2018 guideline update from the American Cancer Society , 2018, CA: a cancer journal for clinicians.

[41]  Zhenwei Dai,et al.  Multi-cohort analysis of colorectal cancer metagenome identified altered bacteria across populations and universal bacterial markers , 2018, Microbiome.

[42]  Chengcheng Hu,et al.  Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles , 2018, Front. Microbiol..

[43]  Ye Chen,et al.  Trimethylamine N-oxide prime NLRP3 inflammasome via inhibiting ATG16L1-induced autophagy in colonic epithelial cells. , 2017, Biochemical and biophysical research communications.

[44]  T. Buford.  (Dis)Trust your gut: the gut microbiome in age-related inflammation, health, and disease , 2017, Microbiome.

[45]  S. Montain,et al.  Changes in intestinal microbiota composition and metabolism coincide with increased intestinal permeability in young adults under prolonged physiological stress. , 2017, American journal of physiology. Gastrointestinal and liver physiology.

[46]  J. Song,et al.  Caveolin‐1 serves as a negative effector in senescent human gingival fibroblasts during Fusobacterium nucleatum infection , 2017, Molecular oral microbiology.

[47]  E. Otsuji,et al.  Serum metabolomics analysis for early detection of colorectal cancer , 2017, Journal of Gastroenterology.

[48]  K. Mansouri,et al.  l-arginine alters the effect of 5-fluorouracil on breast cancer cells in favor of apoptosis. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[49]  Sonia González,et al.  Nutrition and the gut microbiome in the elderly , 2017, Gut microbes.

[50]  S. O'keefe.  Diet, microorganisms and their metabolites, and colon cancer , 2016, Nature Reviews Gastroenterology &Hepatology.

[51]  A. Braune,et al.  Bacterial species involved in the conversion of dietary flavonoids in the human gut , 2016, Gut microbes.

[52]  M. Ufnal,et al.  TMAO: A small molecule of great expectations. , 2015, Nutrition.

[53]  Qiang Feng,et al.  Gut microbiome development along the colorectal adenoma–carcinoma sequence , 2015, Nature Communications.

[54]  A. Krivoruchko,et al.  Microbial acetyl-CoA metabolism and metabolic engineering. , 2015, Metabolic engineering.

[55]  Jiachao Zhang,et al.  A phylo-functional core of gut microbiota in healthy young Chinese cohorts across lifestyles, geography and ethnicities , 2015, The ISME Journal.

[56]  A. Harris,et al.  Acetyl-CoA Synthetase 2 Promotes Acetate Utilization and Maintains Cancer Cell Growth under Metabolic Stress , 2015, Cancer cell.

[57]  G. Hanna,et al.  Tyrosine, Phenylalanine, and Tryptophan in Gastroesophageal Malignancy: A Systematic Review , 2014, Cancer Epidemiology, Biomarkers & Prevention.

[58]  Harry J. Flint,et al.  The gut microbiota, bacterial metabolites and colorectal cancer , 2014, Nature Reviews Microbiology.

[59]  N. Hay,et al.  The pentose phosphate pathway and cancer. , 2014, Trends in biochemical sciences.

[60]  M. Zheng,et al.  Metabonomics identifies serum metabolite markers of colorectal cancer. , 2013, Journal of proteome research.

[61]  A. Sharma,et al.  Anti-cancer potential of flavonoids: recent trends and future perspectives , 2013, 3 Biotech.

[62]  D. Sinderen,et al.  Gut microbiota composition correlates with diet and health in the elderly , 2012, Nature.